Copper Catalyzed Intramolecular N-Arylation of Ketene Aminals at

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Copper Catalyzed Intramolecular N-Arylation of Ketene Aminals at Room Temperature: Synthesis of 2-Amino-3-cyanoindoles ANNARAM THIRUPATHI, Manojkumar Janni, and Saravanan Peruncheralathan J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00816 • Publication Date (Web): 31 May 2018 Downloaded from http://pubs.acs.org on May 31, 2018

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The Journal of Organic Chemistry

Copper Catalyzed Intramolecular N-Arylation of Ketene Aminals at Room Temperature: Synthesis of 2-Amino-3-cyanoindoles Annaram Thirupathi, Manojkumar Janni, and Saravanan Peruncheralathan* School of Chemical Sciences, National Institute of Science Education and Research (NISER) Bhubaneswar, HBNI, Jatni, Khurda – 752050, Odisha, India Email: [email protected]

Abstract

Various 2-amino-3-cyanoindoles are synthesized through a copper catalyzed intramolecular N-arylation of ketene aminals at room temperature for the first time with 60 99% yields within 0.1 - 2 hours. A controlled regioselective N-arylation of unsymmetrical ketene aminals is also studied. Further, a new double heteroannulation approach is demonstrated for the synthesis of 11-amino-indolo[2,3-b]quinolines from acyclic and nonheterocyclic precursors.

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Catalytic organic transformation at ambient temperature is of central importance in the industrial research.1 This transformation can be scaled up to bulk production of agrochemicals, fine materials and drugs. Particularly, the C─N bond forming reactions are widely applied in industry for the synthesis of nitrogen containing fine chemicals and pharmaceuticals.2 Despite well-developed protocols, these reactions use harsh reaction conditions, using coupling reagents, generate waste materials, and longer reaction time. To overcome these drawbacks, transition metal catalyzed C─N bond forming reactions at room temperature are developed3,4 and frequently applied for the synthesis of variety of aryl amines5 and amides.6 However, this approach is less explored in the construction of functionalized heterocyclic compounds.7 Therefore, developing a catalytic C─N cross-coupling reaction at room temperature to access a broad spectrum of N-heterocycles is highly desirable. Recently, arylnitrile containing drugs have attracted considerable attention among medicinal chemists.8 In particular, 1,2-aminocyano arene derivatives have shown interesting biological properties and some of these compounds are in clinical trials.9 The representative examples of these molecules are depicted in Figure 1. Recently, the 2-amino-3-cyanoindole derivative was identified as a selective estrogen ligand -isoform for various diseases associated with estrogen receptor.10 Interestingly, these derivatives were also used as precursors for the synthesis of fused N-rich heterocycles.11 In literature, few methods are reported for the synthesis of 2-amino-3-cyanoindoles.12-14 Generally, the reported methods of these compounds involve step-wise transformations of o-halonitrobenzene13 or o-haloaniline precursors.14 Further, one-step protocol for the synthesis of 2-amino-3-cyano-5hydroxyindoles is developed through Nenitzescu reaction of ketene aminals with 1,4benzoquinone resulting in moderate yields.15 Recently, the palladium catalyzed direct Narylation followed by in situ cyclization of resulting intermediate to 2-amino-3-cyanoindoles was reported.16 However, this reaction failed to give the expected 2-aminoindole in the


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presence of copper(I)iodide.16 Thus, in the context of the limitation of the existing methods such as low yields,15 tedious work-up,12n multi-step synthesis,12f 3-cyanoindole precursor,12j-l and high temperature,12g developing a mild and practical method for the synthesis of 2-amino3-cyanoindoles is vital.

Figure 1. Selective Biological Important 1,2- & 1,4-Amino-cyano Aryl/heteroaryl Derivatives Copper catalyzed C─N bond formation is one of the most powerful methods for the synthesis of indoles and their derivatives.17 Despite the versatility, only a few methods are known for the construction of indoles through N-arylation process.18 These methods suffer high catalyst loading,18b longer reaction time,18a-b and limited substrate scope.18h In addition, the copper catalyzed direct formation of indole ring by N-arylation of ketene aminals at room temperature has not been reported.19 Recently, we have reported a mild and practical method for the synthesis of 2-aminobenzo[b]thiophenes which involves a copper-catalyzed chemoselective intramolecular Ullman reaction at room temperature.20 In continuation of our ongoing interest in chemo- and regioselective synthesis of highly substituted heterocycles,21 herein we report the synthesis of various functionalized 2-amino-3-cyanoindoles at room temperature by copper catalyzed intramolecular N-arylation of ketene aminals for the first time. The regioselective C─N bond formation of unsymmetrical ketene aminals is also studied. The newly synthesized 2-anilino-3-cyanoindoles are transformed to 11-amino-indolo[2,3b]quinolines by Brønsted acid mediated intramolecular Gattermann type cyclization.



The required ketene aminals 3 were prepared by treating anion of 2-bromoaryl acetonitriles 1 with substituted carbodiimides 2 in moderate to good yields (Table 1). All newly synthesized α-cyano-α-(2-bromoaryl)-N,N-acetal derivatives 3 were characterized by spectral and analytical data. Table 1. Synthesis of Ketene Aminals 3a

After having the ketene aminals 3 in our hand, the aminal 3aa was chosen as model substrate for the copper catalyzed intramolecular N-arylation process. The initial experiment was performed with CuI affording 56% of the N-arylated product 4aa after 32 hours (Table 2, Entry 1). Interestingly, when 1,10-phenanthroline was used as a ligand, the yield of the Narylation was significantly increased (96%) and the reaction completed within 5 minutes (Table 2, Entry 2). Various bases like Cs2CO3, K2CO3 and K3PO4 were screened for the effectiveness of the coupling reaction. These conditions afforded the product 4aa ranging from 90-91% yields (Table 2, Entries 3-5). However, bases such as NaOAc and triethylamine were not effective (Table 2, Entries 6-7). The solvent effect on N-arylation process was also examined with different solvents such as THF, dioxane, toluene, DMSO, and DMA. Among these,


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DMSO was comparable with DMF in terms of conversion and yields of 2-amino-3-cyanoindole 4aa (Table 2, Entries 8 -12). Next, various copper salts were studied for the N-arylation reaction. CuCl was found to give a quantitative conversion to the product 4aa in comparision with CuBr and Cu(OAc)2 (Table 2, Entries 13-15) and was chosen for further studies. To finetune the reaction, a set of ligands, BINAM, TMEDA, and L-proline were screened and found to be less beneficial when compared with 1,10-phenanthroline (Table 2, Entries 16-18). Lowering the catalyst loading significantly reduced the yield of the product 4aa and increased the reaction time (Entries 19 and 20). Table 2. Optimization of the N-arylation of Aminal 3aaa,b

With the optimized conditions of the reaction, we studied a series of ketene aminals 3 for the N-arylation process. The N,N-diphenyl N,N-acetal derivative 3ab was smoothly transformed to 1-N-phenyl-2-anilino-3-cyanoindole (4ab) in 90% yield (Table 3).

Similarly,

3-cyano-2-(4-fluoroanilino)indole

4ac

was

obtained

from

the

corresponding ketene aminal 3ac in good yield (74%, Table 3). Interestingly, 2,6-



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dimethylanilino substituted ketene aminal 3ad afforded 4ad in excellent yield (86%, Table 3). These reactions completed within 5 minutes. Table 3. Copper Catalyzed N-Arylation of Ketene Aminals 3 at Room Temperaturea

Next, the electron donating substituent effects on the aryl groups were investigated. The 5,6-dimethoxy substituted 2-amino-3-cyanoindoles 4ba and 4bb were synthesized from the respective ketene aminals in 92% and 88% yields, respectively. However, 5,6-methylenedioxy-2-(4-anisidinyl)indole 4ca was obtained in moderate yield with a longer reaction time (2 h, Table 3). On the other hand, the 2, 6-dimethyl phenyl substituted aminal 3cd gave very good yield of product 4cd within 5 minutes. In the case of the α-(2-bromo-3,6-dimethoxyphenyl) aminals 3dc and 3dd with electron withdrawing and sterically hindered substituents on nitrogen afforded the respective 2amino-3-cyanoindoles 4dc and 4dd in 84-85% yields. naphthyl)-aminal

3ea

was

transformed

to

The α-cyano-α-(1-bromo-21-N-(4-methoxyanilino)-2-(4-

methoxyanilino)-3-cyanobenzo[g]indole (4ea) in 88% yield under the optimized reaction conditions. Whereas, the 4-fluroanilino derivative 3ec gave only 67% of 2amino-3-cyanoindole 4ec (Table 3).


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We then turned our attention to examine the alkyl substituted ketene aminals for intramolecular copper catalyzed N-arylation reaction. The ketene aminal 3ae derived from isopropyl carbodiimide was subjected to undergo the reaction under optimized conditions. To our surprise, the expected 2-amino-3-cyanoindole 4ae was not formed at room temperature. However, the same reaction when performed at 120 oC afforded the 2-isopropylaminoindole 4ae in 80% yield (Table 4). Similarly, the other alkyl amino substituted indole derivatives 4af, 4bf, and 4ce were prepared from the respective aminals 3af, 3bf, and 3ce at 120 oC with short reaction times (30 mins) (Table 4). Table 4. Copper Catalyzed N-Arylation of Alkyl Substituted Ketene Aminals 3

Next we focused on the N-arylation of ketene aminals 3ag and 3ah having unsymmetrical aryl groups (4-MeOPh vs 4-NO2Ph, Table 5). Under the optimized conditions, 3ag resulted in the formation of 3-cyano-2-(4-nitroanilino)indole 4ag in 81% yield, which was confirmed by single crystal X-ray analysis (Table 5). A similar trend was also observed in the ketene aminal 3ah affording 3-cyano-1-N-phenylindole 4ah in 86% yield. Both these unsymmetrical aminals gave an exclusively single regioisomer. It seems that the electron rich nitrogen is arylated faster than the deficient one. These results encouraged us to investigate the alkyl and aryl sybstituted ketene aminal. Thus, we performed an experiment with the alkyl, aryl substituted ketene aminal 3ai at room temperature. As seen above, the N-arylation occurred at the aryl substituted N-atom and the product 4ai was obtained in 68% yield. The structure of 4ai was confirmed by single crystal X-ray analysis (Table 5).



Table 5. Regioselective Copper Catalysed N-Arylation of Unsymmetrical Ketene Aminals 3a

We then turned our interest towards the studies involving α-oxo-ketene aminals (6a and 6c). The required α-oxo-ketene aminals 7 were prepared from reaction of enolate of 2-bromo-benzyl derivatives with cabodiimides (Table 6). The α-oxo-ketene aminals 6ad, 6bb and 6ca derived from the respective ketones 5a, 5b, and 5c, were smoothly transformed to 3-aroxy-2-aminoindoles 7ad, 7bb, and 7ca respectively in moderate to very good yields (Table 6). Table 6. Synthesis of α-Oxo-ketene Aminals 6 and 3-Aroyl-2-aminoindoles 7a

The newly synthesized indole core is decorated with two functional groups at 2- and 3positions, respectively. We envisioned that the electrophilicity of the nitrile can be increased by a Brønsted acid, which could be trapped in situ by an intramolecular attack of aniline moiety at its ortho position. This new strategy would result in the construction of 4-aminoquinoline ring over the indole. To optimize the proposed strategy, we screened a set of Brønsted acids for the intramolecular reaction of 2-anilino-3-cyanoindole 4aa. Interestingly, we found that in


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the presence of triflic acid (10 equiv), the indole 4aa was smoothly converted to the corresponding 11-amino-indolo[2,3-b]quinoline 8aa in 95% yield at room temperature. Using the optimized conditions, several indole derivatives 4 were transformed to the corresponding indolo fused quinolines 8ab, 8ac, 8dc, and 8ea in moderate to very good yields (Table 7). To the best of our knowledge, the construction of indolo[2,3-b]quinolines from an acyclic precursor via double heteroannulation strategy at room temperature is hitherto not reported in literature.22 Table 7. Synthesis of 11-Amino-indolo[2,3-b]quinolines 8a

In conclusion, we have demonstrated a simple and efficient protocol for the synthesis of 2-amino-3-cyanoindoles through the copper catalyzed N-arylation of ketene aminals at room temperature for the first time. This protocol provides various substituted 2-amino-3cyanoindoles in good to excellent yields in short reaction time. In addition, the controlled regioselective N-arylation of unsymmetrical ketene aminals was established. The N-arylation was also extended to α-oxo ketene aminals. Interestingly, the new double heteroaromatic annulation strategy was used to synthesize 11-amino-indolo[2,3-b]quinolines from acyclic precursors at room temperature for the first time.



Experimental Section General Information All reactions were performed by using standard vial technique with rubber septum. All solids were weighed in air. Toluene, Dioxane, DMF, DMSO, DMA, Cs2CO3, K3PO4, NaOAc, DMAP, KOtBu, and Et3N were purchased from Aldrich, Acros, Merck, Spectrochem or AlfaAesar and used as received. CuI, CuBr, CuCl and Cu(OAc)2 were purchased from Aldrich. Carbodiimides were synthesized from respective thioureas, which derived from aniline derivatives and few carbodiimides were purchased from Aldrich. Tetramethylethylenediamine, (R)-(+)-1,1'-binaphthyl-2,2'-diamine, L-proline and 1,10-phenanthroline were purchased from Aldrich. All other reagents were purchased from common suppliers and used without further purification. Flash chromatography was performed using Merck Silica gel (230-400 mesh). Fractions were monitored by thin-layer chromatography on precoated silica gel 60 F254 plates (Merck & co.) and were visualized by UV. NMR data were recorded on Bruker ARX 400 and 700 spectrometers. 13C and 1H NMR spectra were recorded in CDCl3, MeOH-d4 and DMSOd6 referenced according to signals of deutero solvents. ESI HR-MS measurements were performed on Bruker micrOTOF-Q-II mass-spectrometer. General Procedure for the Synthesis of Ketene Aminals 3 & 6 To a stirring suspension of NaH (60% suspension in mineral oil) (0.144 mg, 3.6 mmol, 1.2 equiv) in DMF at 0

oC

was added drop wise the corresponding 2-haloaryl

acetonitrile/deoxybenzoin (3 mmol) in DMF. After being further stirred for 1 h at room temperature, a solution of carbodiimide (3.6 mmol, 1.2 equiv) in DMF was added to the reaction mixture at 0 oC and followed by further stirring for 5 min - 15 h at room temperature. After complete consumption of the starting materials (monitored by TLC), the reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic layer washed with water (3 x 25 mL) and brine (25 mL), dried over anhydrous Na2SO4, and


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concentrated under reduced pressure. The crude products were purified by flash chromatography using hexane and EtOAc as eluent. 2-(2-Bromophenyl)-3,3-bis((4-methoxyphenyl)amino)acrylonitrile (3aa): Yield: 51% (695 mg); White Solid; Rf = 0.34 in 25% EtOAc in Hexanes; Melting Point: 143 – 145 oC; IR (KBr): ν (cm-1) = 3292, 2933, 2171, 1601, 1579, 1510, 1371, 1240, 1031, 822; 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 7.7, 1.4 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.9 Hz, 2H), 7.02 – 6.94 (m, 1H), 6.83 (d, J = 8.9 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 6.59 (d, J = 8.9 Hz, 2H), 6.41 (s, 1H), 5.67 (s, 1H), 3.74 (s, 3H), 3.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.6, 156.4, 153.9, 134.0, 133.3, 133.0, 131.9, 131.5, 128.5, 127.7, 125.9, 123.5, 123.2, 122.0, 114.6, 114.1, 67.1, 55.59, 55.54; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. for C23H21N3O2Br: 450.0812 & 452.0792, found: 450.0814 & 452.0801. 2-(2-Bromophenyl)-3,3-bis(phenylamino)acrylonitrile (3ab): Yield: 66% (775 mg); Pale yellow solid; Rf = 0.31 in 25% EtOAc in Hexanes; Melting Point: 148 – 150 oC; IR (KBr): ν (cm-1) = 3368, 3237, 3050, 2924, 2193, 1573, 1344, 1028, 752; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.4 Hz, 1H), 7.38 – 7.34 (m, 1H), 7.21 (m, 3H), 7.12 – 6.97 (m, 6H), 6.87 (m, 3H), 6.67 (s, 1H), 5.85 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 151.9, 139.2, 138.5, 133.6, 133.5, 132.8, 129.4, 128.9, 128.8, 127.8, 125.7, 123.9, 123.7, 121.4, 120.6, 120.5, 70.3; HRMS (ESITOF) m/z: [M + H]+ Calcd. for C21H17N3Br: 390.0600 & 392.0581, found: 390.0619 & 392.0601. 2-(2-Bromophenyl)-3,3-bis((4-fluorophenyl)amino)acrylonitrile (3ac): Yield: 73% (936 mg); Pale yellow solid; Rf = 0.25 in 25% EtOAc in Hexanes; Melting Point: 217 – 219 oC; IR (KBr): ν (cm-1) = 3376, 3246, 3055, 2192, 1579, 1508, 1215, 831; 1H NMR (400 MHz, DMSOD6) δ 9.06 (s, 1H), 8.69 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.30 (dd, J = 7.6, 1.2 Hz, 1H), 7.24 (t, J = 7.1 Hz, 1H), 7.15 – 7.03 (m, 4H), 7.03 – 6.98 (m, 1H), 6.92 – 6.82 (m, 4H); 13C NMR (100 MHz, DMSO-D6) δ 157.4 (d, J = 238 Hz), 157.3 (d, J = 237 Hz), 152.0, 137.7, 136.4,



135.2, 132.9, 132.3, 127.8, 127.7, 124.2, 121.6, 121.2 (d, J = 7.2 Hz), 120.2 (d, J = 7.2 Hz), 115.4 (d, J = 22.3 Hz), 114.8 (d, J = 22.5 Hz), 69.6; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. for C21H14F2BrN3Na: 448.0231 & 450.0238, found: 448.0238 & 450.0220. 2-(2-Bromophenyl)-3,3-bis((2,6-dimethylphenyl)amino)acrylonitrile (3ad): Yield: 68% (916 mg); White solid; Rf = 0.31 in 25% EtOAc in Hexanes; Melting Point: 176 – 177 oC; IR (KBr): ν (cm-1) = 3374, 3254, 2924, 2174, 1600, 1585, 1470, 1222, 773; 1H NMR (400 MHz, CDCl3, Major isomer only) δ 7.68 (d, J = 8 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.33 (t, J = 6.4 Hz, 1H), 7.19 – 7.16 (m, 3H), 7.11 – 7.07 (m, 2H), 7.04 – 7.03 (m, 2H), 5.57 (s, 1H), 5.22 (s, 1H), 2.46 (s, 6H), 2.35 (s, 6H). 13C NMR (100 MHz, CDCl3, Major isomer only) δ 154.6, 137.6, 134.6, 134.4, 134.3, 133.5, 133.4, 130.6, 129.4, 128.7, 128.5, 128.3 (2C), 128.0, 123.6, 120.6, 60.0, 18.6, 18.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C25H25N3Br: 446.1226 & 448.1207, found: 446.1245 & 448.1228. 2-(2-Bromophenyl)-3,3-bis(isopropylamino)acrylonitrile (3ae): Yield: 50% (489 mg); White solid; Rf = 0.38 in 30% EtOAc in Hexanes; Melting Point: 101 – 104 oC; IR (KBr): ν (cm-1) = 3328, 3089, 2967, 2158, 1604, 1561, 1479, 1304, 1144, 1023, 741; 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.8 Hz, 1H), 7.43 – 7.20 (m, 2H), 7.10 (t, J = 7.3 Hz, 1H), 4.25 3.23 (m, 4H), 1.16 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 160.1, 134.8, 133.4, 133.3, 128.7, 127.8, 126.8, 123.2, 64.3, 46.7(2C), 23.5(2C); HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C15H21N3Br: 322.0913 & 324.0893, found: 322.0939 & 324.0923. 2-(2-Bromophenyl)-3,3-bis(cyclohexylamino)acrylonitrile (3af): Yield: 42% (499 mg); White solid; Rf = 0.3 in 15% EtOAc in Hexanes; Melting Point: 100 – 102 oC; IR (KBr): ν (cm1)

= 3307, 2930, 2853, 2157, 1527, 1470, 1450, 1342; 1H NMR (400 MHz, CDCl3) δ 7.59 (d,

J = 7.3 Hz, 1H), 7.34 - 7.24(m, 2H), 7.11 - 7.08 (m, 1H), 3.72 – 4.21 (m, 2H), 3.05 – 3.42 (m, 2H), 1.93 (s, 4H), 1.47 - 4.47 (m, 6H), 1.30 - 1.97 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 159.9, 135.1, 133.1, 128.2, 127.6, 126.6, 123.65, 123.6, 62.6, 53.4(2C), 33.7(2C), 25.2(2C),


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24.7(2C); HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C21H29BrN3: 402.1539 & 404.1520 found: 402.1560 & 404.1545. (E)&(Z)-2-(2-Bromophenyl)-3-((4-methoxyphenyl)amino)-3-((4nitrophenyl)amino)acrylo nitrile (3ag): Yield: 59% (815 mg); Yellowish orange solid; Rf = 0.33 in 40% EtOAc in Hexanes; Melting Point: 109 – 111 oC; IR (KBr): ν (cm-1) = 3371, 2928, 2370, 2184, 1595, 1510, 1333, 1305, 1248, 1179, 1111; 1H NMR (400 MHz, CDCl3, Mixture of two isomers in the ratio of ≅ 1 : 1.1) δ 8.03 – 7.97 (m, 2H) [7.91 – 7.86 (m, 2H)], 7.58 – 7.55 (m, 1H) [7.49 – 7.46 (m, 1H)], 7.42 – 7.39 (m, 1H), 7.34 – 7.29 (m, 3H), [7.19 – 7.08 (m, 4H)], 7.02 -6.97 (m, 3H) [ 6.91 – 6.85 (m, 3H)], 6.77 – 6.71 (m, 2H), [6.65 – 6.59 (m, 2H)], 6.20 (s, 1H) [6.00 (s, 1H)], 3.71 (s, 3H), [3.66 (s, 3H)]; 13C NMR (100 MHz, CDCl3, Mixture of two isomers) δ 156.9 (156.8), 151.0 (150.9), 146.2 (145.2), 142.8 (142.2),133.7 (133.6), 132.9 (132.8), 132.7 (132.4), 131.3 (130.8), 129.6 (129.2), 128.3 (128.0), 127.3 (125.7), 125.3 (124.9), 123.09 (123.02), 120.7 (118.2), 117.9 (114.7), 114.4 (114.2), 73.3 (72.7), 55.6 (55.4); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. For C22H17BrN4O3Na: 487.0376 & 489.0357, found: 487.0396 & 489.0374. (E)&(Z)-2-(2-Bromophenyl)-3-((4-nitrophenyl)amino)-3-(phenylamino)acrylonitrile (3ah): Yield: 65% (852 mg); Yellowish orange solid; Rf = 0.32 in 33% EtOAc in Hexanes; Melting Point: 129 – 131 oC; IR (KBr): ν (cm-1) = 3385, 2924, 2366, 2186, 1596, 1499, 1330, 1258, 1181, 1112, 848, 751; 1H NMR (400 MHz, CDCl3, Mixture of two isomers in the ratio of ≅ 1 : 1.2) δ 8.01 (d, J = 9.0 Hz, 2H) [7.90 (d, J = 9.0 Hz, 2H)], 7.58 (d, J = 8.0 Hz, 1H) [ 7.50 (d, J = 8.0 Hz, 1H)], 7.41 (dd, J = 7.7, 1.2 Hz, 1H) [7.38 – 7.35 (m, 1H)], 7.34 – 7.31 (m, 1H) [7.31– 7.26 (m, 1H)], 7.23 - 7.18 (m, 3H), [7.15 -7.08 (m, 6H)], 7.06 – 6.98 (m, 3H), 6.94 - 6.89 (m, 2H) [6.94 - 6.89 (m, 2H)], 6.20 (s, 1H) [6.05 (s, 1H)]. 13C NMR (100 MHz, CDCl3, Mixture of two isomers) δ 150.25 (150.22), 146.36 (146.32), 145.36 (145.32), 142.07 (142.05), 141.88 (141.85), 138.7 (138.0), 133.64 (132.8), 132.6 (132.4), 129.5 (129.45), 129.2 (129.1),



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128.1 (127.9) 125.5 (125.2), 125.1 (124.8), 124.2 (124.1), 120.6 (120.3), 118.2 (117.8), 74.5 (74.1); HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. For C21H15BrN4O2Na: 457.0271 & 459.0251, found: 457.0273 & 459.0252. (E)&(Z)-2-(2-Bromophenyl)-3-(tert-butylamino)-3-(phenylamino)acrylonitrile

(3ai):

Yield: 60% (660 mg); Yellow solid; Rf = 0.29 in 25% EtOAc in Hexanes; Melting Point: 134 – 135 oC; IR (KBr): ν (cm-1) = 3393, 3295, 2964, 2369, 2172, 1570, 1421, 1394, 1286, 1229; 1H

NMR (700 MHz, CDCl3, Mixture of two isomers in the ratio of ≅ 1 : 0.4) 7.29 (d, J = 7.7

Hz, 1H), 7.23 – 7.10 (m, 2H), 7.14 (d, J = 7.7 Hz, 1H), 7.01 – 6.81 (m, 2H), 6.83 – 6.75 (m, 3H), 5.65 (s, 1H), 4.6 (s, 1H), 1.40 (s, 9H);13C NMR (175 MHz, CDCl3, Major isomer only) δ 156.3, 139.2, 134.0, 133.1, 132.1, 128.6, 128.1, 127.3, 124.8, 122.9, 122.6, 119.7, 72.8, 55.0, 31.1; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. For C19H20BrN3Na: 392.0733 & 394.0713, found: 392.0704 & 394.0689. 2-(2-Bromo-4,5-dimethoxyphenyl)-3,3-bis((4-methoxyphenyl)amino)acrylonitrile (3ba): Yield: 54% (827 mg); Yellow solid; Rf = 0.35 in 30% EtOAc in Hexanes; Melting Point: 148 – 150 oC; IR (KBr): ν (cm-1) = 3339, 2931, 2835, 2169, 1608, 1504, 1245, 1172, 827; 1H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 8.8 Hz, 2H), 6.95 (s, 1H), 6.85 (d, J = 8.8 Hz, 2H), 6.81 (s, 1H), 6.76 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 6.33 (s, 1H), 5.68 (s, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.74 (s, 3H), 3.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.5, 156.4, 153.9, 148.7, 148.5, 132.1, 131.6, 125.7, 123.3, 123.2, 122.1, 116.4, 115.7, 115.0, 114.5, 114.1, 67.0, 56.2, 56.1, 55.5(2C); HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C25H25N3O4Br: 510.1023 & 512.1004, found: 510.1034 & 512.1021. 2-(2-Bromo-4,5-dimethoxyphenyl)-3,3-bis(phenylamino)acrylonitrile (3bb): Yield: 59% (795 mg); Pale yellow solid; Rf = 0.32 in 30% EtOAc in Hexanes; Melting Point: 196 – 198 oC;

IR (KBr): ν (cm-1) = 3374, 3332, 2928, 2169, 1600, 1497, 1432, 1245, 1172, 1014, 746;

1H

NMR (400 MHz, CDCl3) δ 7.21 (t, J = 7.7 Hz, 2H), 7.12 – 7.02 (m, 4H), 7.03 – 6.94 (m,


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2H), 6.93– 6.83 (m, 3H), 6.82 (s, 1H), 6.57 (s, 1H), 5.89 (s, 1H), 3.80 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.8, 148.9, 148.6, 139.3, 138.8, 129.3, 129.0, 128.9, 125.3, 123.7, 121.5, 120.4, 120.3, 116.2, 115.7, 114.7, 70.2, 56.2, 56.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C23H21N3O2Br: 450.0812 & 452.0792, found: 450.0803 & 452.0790. 2-(2-Bromo-4,5-dimethoxyphenyl)-3,3-bis(cyclohexylamino)acrylonitrile (3bf): Yield: 29% (406 mg); White solid; Rf = 0.28 in 25% EtOAc in Hexanes; Melting Point: 137 – 138 oC;

IR (KBr): ν (cm-1) = 3692, 3339, 2931, 2852, 2150, 1541, 1500, 1435, 1209; 1H NMR (700

MHz, CDCl3) δ 7.02 (s, 1H), 6.77 (s, 1H), 4.10 (brs, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.59 (brs, 1H), 3.36 – 3.23 (m, 1H), 3.05 – 2.91 (m, 1H), 2.07 – 1.95 (m, 2H), 1.86 – 1.73 (m, 4H), 1.64 – 1.51 (m, 4H), 1.28 – 0.95 (m, 10 H); 13C NMR (175 MHz, CDCl3) δ 160.1, 148.9, 148.5, 126.4, 123.4, 117.4, 115.6, 115.4, 63.7, 56.1, 56.1, 54.4, 53.1, 48.8, 34.0, 33.9, 25.6, 25.3, 24.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C23H33BrN3O2: 462.1751 & 464.1731, found: 462.1731 & 464.1712. 2-(6-Bromobenzo[d][1,3]dioxol-5-yl)-3,3-bis((4-methoxyphenyl)amino)acrylonitrile (3ca): Yield: 58% (866 mg); Yellow solid; Rf = 0.32 in 30% EtOAc in Hexanes; Melting Point: 154 – 155 oC; IR (KBr): ν (cm-1) = 3261, 2913, 2161, 1510, 1470, 1242, 1028, 828; 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J = 8.8 Hz, 2H), 6.94 (s, 1H), 6.84 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H), 6.76 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 8.8 Hz, 2H), 6.33 (s, 1H), 5.91 (s, 2H), 5.62 (s, 1H), 3.74 (s, 3H), 3.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.7, 156.5, 154.0, 147.8, 147.6, 131.9, 131.5, 126.6, 123.6, 123.5, 121.8, 117.3, 114.6, 114.2, 113.0, 112.2, 102.0, 67.1, 55.6, 55.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C24H21N3O4Br: 494.0710 & 496.0691, found: 494.0691 & 496.0681. 2-(6-Bromobenzo[d][1,3]dioxol-5-yl)-3,3-bis((2,6-dimethylphenyl)amino)acrylonitrile (3cd): Yield: 62% (910 mg); White solid; Rf = 0.3 in 20% EtOAc in Hexanes; Melting Point: 117 – 118 oC; IR (KBr): ν (cm-1) = 3377, 3261, 2920, 2176, 1585, 1474, 1223, 1035; 1H NMR



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(400 MHz, CDCl3, Major isomer only) 7.13 – 7.09 (m, 2H), 7.07 – 7.02 (m, 4H), 7.00 (s, 1H), 6.86 (s, 1H), 5.94 (s, 2H), 5.47 (s, 1H), 5.19 (s, 1H), 2.37 (s, 6H), 2.29 (s, 6H);13C NMR (100 MHz, CDCl3, Major isomer only) δ 154.7, 148.4, 147.7, 137.76, 137.70, 134.0, 128.7, 128.47, 128.42, 128.1, 127.3, 123.6, 119.5, 115.4, 113.4, 113.1, 102.0, 59.7, 18.7, 18.5; HRMS (ESITOF) m/z: [M + H]+ Calcd. For C26H25N3O2Br; 490.1125 & 492.1106, found: 490.1136 & 492.1120. 2-(6-Bromobenzo[d][1,3]dioxol-5-yl)-3,3-bis(isopropylamino)acrylonitrile (3ce): Yield: 42% (461 mg); Pale yellow solid; Rf = 0.3 in 25% EtOAc in Hexanes; Melting Point: 116-118 oC;

IR (KBr): ν (cm-1) = 3394, 3307, 2972, 2930, 2152, 1572, 1552, 1477, 1034; 1H NMR (400

MHz, CDCl3) δ 7.06 (s, 1H), 6.77 (s, 1H), 5.98 (s, 2H), 4.0 – 3.89 (m, 1H), 3.76 – 3.63 (m, 1H), 3.43 (brs, 2H), 1.21 (s, 6H), 0.96 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 160.2, 147.9, 147.6, 127.2, 123.1, 117.9, 112.9, 112.4, 101.9, 64.4, 47.4, 46.1, 23.5(2C); HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C16H21N3O2Br: 366.0812 & 368.0792, found: 366.0816 & 368.0797. 2-(2-Bromo-3,5-dimethoxyphenyl)-3,3-bis((4-fluorophenyl)amino)acrylonitrile

(3dc):

Yield: 59% (858 mg); Pale yellow solid; Rf = 0.25 in 30% EtOAc in Hexanes; Melting Point: 161 – 163 oC; IR (KBr): ν (cm-1) = 3406, 3319, 2930, 2173, 1585, 1509, 1336, 1215, 1156; 1H NMR (400 MHz, CDCl3) δ 7.03-6.98 (m, 2H), 6.92 – 6.82 (m, 4H), 6.75 (t, J = 8.5 Hz, 2H), 6.60 (s, 1H), 6.55 (d, J = 2.4 Hz, 1H), 6.34 (d, J = 2.4 Hz, 1H), 5.76 (s, 1H), 3.83 (s, 3H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.9, 159.2 (d, J = 242 Hz), 158.6 (d, J = 255 Hz), 157.3, 152.9, 135.2 (d, J = 2.4 Hz), 134.9, 134.5 (d, J = 2.4 Hz), 122.9 (d, J = 8.2 Hz), 122.6 (d, J = 8.1 Hz), 121.4, 115.9 (d, J = 22.8 Hz), 115.5 (d, J = 22.8 Hz), 108.5, 106.4, 99.1, 69.8, 56.4, 55.7; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. For C23H18F2BrN3O2Na: 508.0443 & 510.0423, found: 508.0457 & 510.0442. 2-(2-Bromo-3,5-dimethoxyphenyl)-3,3-bis((2,6-dimethylphenyl)amino)acrylonitrile (3dd): Yield: 75% (1.143 g); White solid; Rf = 0.32 in 25% EtOAc in Hexanes; Melting Point:


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166 – 167 oC; IR (KBr): ν (cm-1) = 3365, 3250, 2926, 2176, 1581, 1451, 1340, 1025; 1H NMR (400 MHz, CDCl3, Major isomer only) δ 7.10 – 7.07 (m, 2H), 7.06 – 6.94 (m, 4H), 6.64 (s, 1H), 6.42 (s, 1H), 5.43 (s, 1H), 5.25 (s, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 2.38 (s, 6H), 2.28 (s, 6H);

13C

NMR (100 MHz, CDCl3, Major isomer only) δ 159.9, 157.5, 154.4, 137.6, 137.5,

136.7, 136.3, 134.4, 133.5, 128.6, 128.2, 128.1, 120.5, 110.0, 105.7, 99.4, 60.3, 56.4, 55.6, 18.6, 18.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C27H29N3O2Br: 506.1438 & 508.1419, found: 506.1436 & 508.1421. 2-(1-Bromonaphthalen-2-yl)-3,3-bis((4-methoxyphenyl)amino)acrylonitrile (3ea): Yield: 40% (603 mg); Pale red solid; Rf = 0.38 in 30% EtOAc in Hexanes; Melting Point: 106 – 109 oC;

IR (KBr): ν (cm-1) = 3361, 2931, 2834, 2170, 1604, 1582, 1510, 1242, 1179, 1035, 821; 1H

NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.56 – 7.52 (m, 1H), 7.49 – 7.45 (m, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.10 – 7.05 (m, 2H), 6.85 – 6.80 (m, 2H), 6.80 – 6.75 (m, 2H), 6.54 – 6.50 (m, 2H), 6.48 (s, 1H), 5.72 (s, 1H), 3.74 (s, 3H), 3.57 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.6, 156.3, 154.1, 133.3, 132.9, 132.1, 132.0, 131.4, 129.5, 128.0, 128.0, 127.6, 127.5, 126.6, 125.8, 123.4, 123.1, 121.9, 114.6, 114.0, 68.7, 55.5, 55.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C27H23N3O2Br: 500.0968 & 502.0949, found: 500.0963 & 502.0944. 2-(1-Bromonaphthalen-2-yl)-3,3-bis((4-fluorophenyl)amino)acrylonitrile (3ec): Yield: 56% (805 mg); Pale yellow solid; Rf = 0.30 in 25% EtOAc in Hexanes; Melting Point: 131 – 133 oC; IR (KBr): ν (cm-1) = 3265, 2925, 2184, 1587, 1508, 1320, 1217, 1156; 1H NMR (700 MHz, DMSO-D6) δ 9.15 (s, 1H), 8.76 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.67 – 7.56 (m, 1H), 7.56 – 7.48 (m, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.21 – 7.11 (m, 2H), 7.11 – 7.02 (m, 2H), 6.98 – 6.88 (m, 2H), 6.87 – 6.75 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 157.9 (d, J = 236.9 Hz), 157.8 (d, J = 236.7 Hz), 152.9, 138.2, 137.0, 134.2, 133.1, 132.7, 129.9, 128.6, 128.34, 128.31, 127.1 (d, J = 2.45 Hz), 126.8 (d, J = 2.5 Hz), 124.1, 122.0, 121.7 (d, J



= 4.3 Hz), 120.8 (d, J = 5.0 Hz), 116.6 (d, J = 22.2 Hz), 115.4 (d, J = 21.8 Hz), 71.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C25H17BrF2N3: 476.0568 & 478.0549, found: 476.0589 & 478.0577. 2-(2-Bromophenyl)-3,3-bis((2,6-dimethylphenyl)amino)-1-phenylprop-2-en-1-one (6ad): Yield: 44% (684 mg); Yellow solid; Rf = 0.30 in 10% EtOAc in Hexanes; Melting Point: 158 – 160 oC; IR (KBr): ν (cm-1) = 3328, 3237, 2921, 1948, 1583, 1470, 1311, 1211, 1025, 766; 1H NMR (400 MHz, CDCl3, Major isomer only) δ 8.17 – 8.94(m, 1H), 7.64 – 7.40(m, 2H), 7.40 – 7.23 (m, 3H), 7.20 – 6.94 (m, 6H), 6.94 – 6.70 (m, 3H), 6.58 – 6.52 (m, 1H), 5.6 (s, 1H), 2.6 – 1.9 (m, 12H); 13C NMR (100 MHz, CDCl3, Major isomer only) δ 195.4, 162.0, 142.8, 138.7, 136.2, 136.0, 135.8, 134.2, 133.0, 131.7, 130.3, 130.0, 129.4, 128.9, 128.6, 128.4, 128.2, 128.0, 127.8, 125.4, 97.9, 18.6, 18.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C31H30N2OBr: 525.1536 & 527.1517, found: 525.1508 & 527.1494. 2-(2-Bromo-4,5-dimethoxyphenyl)-1-phenyl-3,3-bis(phenylamino)prop-2-en-1-one (6bb): Yield: 39% (625 mg); Yellow solid; Rf = 0.30 in 30% EtOAc in Hexanes; Melting Point: 156 – 158 oC; IR (KBr): ν (cm-1) = 3316, 3054, 2931, 2839, 1599, 1500, 1323, 1234, 1027; 1H NMR (700 MHz, CDCl3, Major isomer only) δ 14.06 (s, 1H), 7.28 – 7.24 (m, 2H), 7.19 - 7. 11(m, 4H), 7.10 – 6.93 (m, 7H), 6.91 – 6.78 (m, 3H), 6.64 (s, 1H), 6.08 (s, 1H), 3.82 (s, 3H), 3.60 (s, 3H); 13C NMR (175 MHz, CDCl3, Major isomer only) δ 190.0, 156.4, 149.0, 148.6, 142.8, 138.4, 129.9, 129.1, 128.6, 128.4, 128.1, 127.5, 127.1, 124.3, 123.0, 122.2, 121.9, 119.2, 118.0, 115.4, 100.2, 56.1, 56.1; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C29H26BrN2O3: 529.1121 & 531.1102, found: 529.1120 & 531.1108. 1-(Benzo[d][1,3]dioxol-5-yl)-2-(6-bromobenzo[d][1,3]dioxol-5-yl)-3,3-bis((4-methoxy phenyl)amino)prop-2-en-1-one (6ca): Yield: 41% (753 mg); Yellow solid; Rf = 0.33 in 40% EtOAc in Hexanes; Melting Point: 159 – 161 oC; IR (KBr): ν (cm-1) = 3394, 2912, 1608, 1509, 1244, 1036, 933, 825; 1H NMR (400 MHz, CDCl3, Major isomer only) δ 13.88 (s, 1H), 7.00


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(s, 1H), 6.98 – 6.89 (m, 2H), 6.86 (s, 1H), 6.82 – 6.72 (m, 4H), 6.68 (s, 1H), 6.62 – 6.4 (m, 3H), 6.53 – 6.44 (m, 2H), 5.98 – 5.94 (m, 2H), 5.89 (s, 2H), 3.67 (s, 3H), 3.65 (s, 3H);

13C

NMR (175 MHz, CDCl3, Major isomer only) δ 187.6, 158.1, 156.7, 147.9, 147.8, 147.5, 146.8, 137.1, 131.3, 125.1, 124.8, 121.9, 120.0, 114.7, 114.4, 113.8 (2C), 112.9, 108.3, 108.1, 107.2, 102.2, 101.9, 100.9, 99.1, 55.5, 55.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C31H26N2O7Br: 617.0918 & 619.0899, found: 617.0924 & 619.0908. Procedure for Optimization of the N-Arylation of Ketene Aminal 3aa An oven-dried 8 mL reaction vial was charged with copper-salt (1-5 mol%), ligand (210 mol%) and base (0.75 mmol, 1.2 equiv), respective aminal 3aa (0.5 mmol) in solvent (2.0 mL) was stirred at room temperature for 5 min – 3 h. The reaction mixture was monitored by TLC. After the starting material had been completely consumed, the reaction mixture was purified by flash chromatography using hexane and EtOAc as eluent. General Procedure for Copper Catalyzed N-Arylation of Ketene Aminals 3 & 6 An oven-dried 8 mL reaction vial was charged with CuCl (5 mol%, 2.47 mg), 1,10Phenanthroline (10 mol%, 9 mg) and KOtBu (0.75 mmol, 1.2 equiv, 0.112 g), the respective ketene aminal 3 (0.5 mmol) in DMF (2.0 mL) was stirred at room temperature / 120 ºC for 5 min - 2 h. The reaction mixture was monitored by TLC. After the starting material had been completely consumed, the reaction mixture was purified by flash chromatography using hexane and EtOAc as eluent. 3-Cyano-1-(4-methoxyphenyl)-2-((4-methoxyphenyl)amino)-1H-indole (4aa): Yield: 99% (183 mg); Pale brick red colour solid; Rf = 0.36 in 25% EtOAc in Hexanes; Melting Point: 121 – 123 oC; IR (KBr): ν (cm-1) = 3337, 2931, 2195, 1561, 1514, 1253, 1029, 829; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.6 Hz, 1H), 7.38 – 7.34 (m, 2H), 7.21 – 7.17 (m, 1H), 7.17 – 7.12 (m, 2H), 7.12 – 7.07 (m, 3H), 6.92 – 6.86 (m, 3H), 5.80 (br s, 1H), 3.89 (s, 3H), 3.80 (s, 3H);



13C

NMR (100 MHz, CDCl3) δ 160.4, 157.6, 148.7, 134.6, 131.3, 129.5, 127.7, 126.4, 125.1,

122.2, 121.7, 117.6, 116.0, 115.7, 114.6, 109.6, 67.8, 55.7, 55.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C23H20N3O2: 370.1550, found: 370.1552. 3-Cyano-1-phenyl-2-(phenylamino)-1H-indole (4ab): Yield: 90% (140 mg); Pale brick red colour solid; Rf = 0.34 in 25% EtOAc in Hexanes; Melting Point: 178 – 179 oC; IR (KBr): ν (cm-1) = 3444, 3265, 2919, 2212, 1559, 1220, 748; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 1H), 7.59 (t, J = 7.6 Hz, 2H), 7.55 – 7.49 (m, 1H), 7.43 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.27 - 7.23 (m, 1H), 7.19 – 7.06 (m, 4H), 7.03 (d, J = 8.0 Hz, 1H), 5.94 (s, 1H); 13C

NMR (100 MHz, CDCl3) δ 146.3, 139.3, 134.4, 134.3, 130.5, 129.6, 129.4, 127.9, 127.4,

124.41, 122.7, 122.5, 120.6, 118.2, 115.7, 110.1, 71.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C22H15N3: 310.1339, found: 310.1353. 3-Cyano-1-(4-fluorophenyl)-2-((4-fluorophenyl)amino)-1H-indole (4ac): Yield: 74% (128 mg); White solid; Rf = 0.40 in 25% EtOAc in Hexanes; Melting Point: 188 – 189 oC; IR (KBr): ν (cm-1) = 3277, 3056, 2210, 1563, 1510, 1212, 832; 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.6 Hz, 1H), 7.49 – 7.36 (m, 2H), 7.32 – 7.21 (m, 3H), 7.18 – 7.11 (m, 1H), 7.11 - 7.05 (m, 2H), 7.04 - 6.93 (m, 3H), 5.92 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 162.8 (d, J = 250.8 Hz), 159.9 (d, J = 244.3 Hz), 147.3, 135.1 (d, J = 2.5 Hz), 134.4, 130.2 (d, J = 2.9 Hz), 130.0 (d, J = 8.8 Hz), 127.2, 123.5 (d, J = 8.2 Hz), 122.7, 122.5, 118.0, 117.6 (d, J = 23.0 Hz), 116.2 (d, J = 22.9 Hz), 115.5, 109.8, 70.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C21H14F2N3: 346.1150, found: 346.1154. 3-Cyano-1-(2,6-dimethylphenyl)-2-((2,6-dimethylphenyl)amino)-1H-indole (4ad): Yield: 86% (157 mg); Brick red colour solid; Rf = 0.31 in 25% EtOAc in Hexanes; Melting Point: 225 – 228 oC; IR (KBr): ν (cm-1) = 3266, 3026, 2921, 2192, 1596, 1560, 1519, 1469, 1202, 767; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.7 Hz, 1H), 7.45 – 7.39 (m, 1H), 7.36-7.31 (m, 2H), 7.21 (m, 1H), 7.16 7.12 (m, 3H), 7.03 (t, J = 7.6 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H),


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5.41 (s, 1H), 2.29 (s, 6H), 2.12 (s, 6H);

13C

NMR (100 MHz, CDCl3) δ 148.2, 138.5, 137.3,

133.9, 132.8, 131.2, 130.4, 129.5, 128.7, 128.6, 128.2, 122.0, 121.4, 117.4, 115.1, 108.7, 64.4, 18.3, 17.7; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C25H24N3: 366.1965, found: 366.1970. 3-Cyano-5,6-dimethoxy-1-(4-methoxyphenyl)-2-((4-methoxyphenyl)amino)-1H-indole (4ba): Yield: 92% (198 mg); Brick red colour solid; Rf = 0.37 in 30% EtOAc in Hexanes; Melting Point: 195 – 197 oC; IR (KBr): ν (cm-1) = 3322, 2932, 2194, 1567, 1519, 1490, 1252, 1186, 1026; 1H NMR (400 MHz, DMSO-D6) δ 8.15 (s, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.99 (m, 3H), 6.81 (d, J = 8.8 Hz, 2H), 6.51 (s, 1H), 3.82 (s, 3H), 3.81 (s, 3H), 3.70 (s, 3H), 3.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.2, 157.0, 147.1, 146.7, 146.5, 132.4, 129.3, 128.3, 126.8, 123.7, 120.1, 116.3, 115.7, 114.6, 100.5, 94.6, 69.4, 56.6, 56.5, 55.7, 55.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C25H24N3O4: 430.1761, found: 430.1786. 3-Cyano-5,6-dimethoxy-1-phenyl-2-(phenylamino)-1H-indole (4bb): Yield: 88% (163 mg); Brick red colour solid; Rf = 0.34 in 30% EtOAc in Hexanes; Melting Point: 179 – 180 oC; IR (KBr): ν (cm-1) =3347, 2936, 2214, 1602, 1487, 1384, 1280, 1167; 1H NMR (400 MHz, CDCl3) δ 7.56 - 7.49 (m, 3H), 7.40 - 7.39 (m, 2H), 7.26 (s, 2H), 7.10 (s, 1H), 6.99 - 6.98 (m, 3H), 6.57 (s, 1H), 5.80 (s, 1H), 3.95 (s, 3H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 147.2, 147.0, 144.1, 140.7, 134.7, 130.3, 129.3, 129.3, 128.0, 127.6, 123.0, 119.7, 118.7, 115.9, 100.6, 94.6, 74.4, 56.5, 56.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C23H20N3O2: 370.1550, found: 370.1554. 3-Cyano-5,6-methylenedioxy-1-(4-methoxyphenyl)-2-((4-methoxyphenyl)amino)-1Hindole (4ca): Yield: 60% (125 mg,); Reddish black colour solid; Rf = 0.33 in 30% EtOAc in Hexanes; Melting Point: 174 – 176 oC; IR (KBr): ν (cm-1) = 3353, 2912, 2202, 1514, 1338, 1254, 1164, 1034, 836; 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.7 Hz, 2H), 7.07 – 7.03 (m, 4H), 6.98 (s, 1H), 6.84 (d, J = 8.7 Hz, 2H), 6.43 (s, 1H), 5.90 (s, 2H), 5.65 (s, 1H), 3.87 (s, 3H),



3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.3, 157.0, 147.0, 144.5, 144.4, 132.5, 129.3, 129.0, 126.7, 123.6, 121.1, 116.0, 115.7, 114.6, 100.9, 97.8, 92.0, 70.2, 55.8, 55.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C24H20N3O4: 414.1448, found: 414.1434. 3-Cyano-5,6-methylenedioxy-1-(2,6-dimethylphenyl)-2-((2,6-dimethylphenyl)amino)1H-indole (4cd): Yield: 85% (174 mg); Reddish black colour solid; Rf = 0.3 in 20% EtOAc in Hexanes; Melting Point: More than 285 oC; IR (KBr): ν (cm-1) = 3353, 2922, 2855, 2202, 1562, 1472, 1280, 1166, 1036; 1H NMR (400 MHz, CDCl3) δ 7.43 – 7.37 (m, 1H), 7.33-7.31 (m, 2H), 7.22 – 7.16 (m, 1H), 7.13-7.11 (m, 2H), 6.95 (s, 1H), 6.16 (s, 1H), 5.88 (s, 2H), 5.24 (s, 1H), 2.27 (s, 6H), 2.12 (s, 6H);

13C

NMR (100 MHz, CDCl3) δ 147.2, 144.0, 143.9, 138.4,

137.1, 134.2, 131.3, 130.4, 129.5, 128.6, 128.5, 127.0, 121.7, 115.2, 100.8, 98.0, 91.2, 65.1, 18.3, 17.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C26H24N3O2: 410.1863, found: 410.1856. 3-Cyano-1-(4-fluorophenyl)-2-((4-fluorophenyl)amino)-5,7-dimethoxy-1H-indole (4dc): Yield: 84% (170 mg); White colour solid; Rf = 0.28 in 33% EtOAc in Hexanes; Melting Point: 242 - 244 oC; IR (KBr): ν (cm-1) = 3293, 2205, 1560, 1542, 1510, 1308, 1213, 1015, 820; 1H NMR (400 MHz, DMSO-D6) δ 8.30 (s, 1H), 7.48-7.42 (m, 2H), 7.28 (t, J = 8.7 Hz, 2H), 7.087.04(m, 4H), 6.55 (d, J = 1.8 Hz, 1H), 6.36 (d, J = 1.8 Hz, 1H), 3.79 (s, 3H), 3.51 (s, 3H); 13C NMR (100 MHz, DMSO-D6) δ 161.7 (d, J = 244.9 Hz), 157.6 (d, J = 242.7 Hz), 156.4, 147.8, 147.0, 138.2, 132.9, 130.9 (d, J = 8.8 Hz), 128.7, 120.7 (d, J = 7.8 Hz), 117.6, 115.5 (d, J = 14.0 Hz), 115.3, 115.2 (d, J = 24.8 Hz), 95.5, 91.8, 73.1, 55.7, 55.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C23H18F2N3O2: 406.1362, found: 406.1341. 3-Cyano-1-(2,6-dimethylphenyl)-2-((2,6-dimethylphenyl)amino)-5,7-dimethoxy-1Hindole (4dd): Yield: 93% (198 mg); Brick red colour solid; Rf = 0.35 in 25% EtOAc in Hexanes; Melting Point: 236 - 238 oC; IR (KBr): ν (cm-1) = 3353, 3003, 2923, 2199, 1620, 1595, 1558, 1151; 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.30 (m, 1H), 7.25-7.22 (m, 2H), 7.20


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– 7.16 (m, 1H), 7.12-7.10 (m, 2H), 6.60 (d, J = 1.9 Hz, 1H), 6.20 (d, J = 1.9 Hz, 1H), 5.26 (s, 1H), 3.82 (s, 3H), 3.49 (s, 3H), 2.26 (s, 6H), 2.13 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 156.4, 147.8, 146.9, 137.9, 137.3, 134.1, 134.1, 130.2, 129.5, 128.63, 128.60, 128.5, 116.0, 115.4, 94.3, 92.4, 65.5, 55.9, 55.9, 18.3, 17.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C27H28N3O2: 426.2176, found: 426.2181. 3-Cyano-1-(4-methoxyphenyl)-2-((4-methoxyphenyl)amino)-1H-benzo[g]indole

(4ea):

Yield: 88% (185 mg); Pale red colour solid; Rf = 0.39 in 25% EtOAc in Hexanes; Melting Point: 206 - 208 oC; IR (KBr): ν (cm-1) = 3342, 2933, 2836, 2199, 1562, 1512, 1245, 1031, 813; 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7.32 - 7.28 (m, 1H), 7.22 – 7.08 (m, 5H), 7.01 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.5 Hz, 2H), 5.58 (s, 1H), 3.96 (s, 3H), 3.80 (s, 3H); 13C NMR (175 MHz, CDCl3) δ 161.0, 157.4, 147.8, 132.1, 131.0, 130.5, 129.4, 128.8, 126.7, 125.7, 124.6, 124.5, 123.4, 123.3, 121.6, 119.7, 117.6, 116.1, 115.8, 114.6, 70.4, 55.8, 55.5; HRMS (ESITOF) m/z: [M + H]+ Calcd. For C27H22N3O2: 420.1707, found: 420.1699. 3-Cyano-1-(4-fluorophenyl)-2-((4-fluorophenyl)amino)-1H-benzo[g]indole (4ec): Yield: 67% (133 mg); Brick red colour solid; Rf = 0.37 in 25% EtOAc in Hexanes; Melting Point: 254 - 256 oC; IR (KBr): ν (cm-1) = 3395, 2211, 1542, 1510, 1227, 822; 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 1H), 7.76-7.65 (m, 2H), 7.51-7.46 (m, 2H), 7.38-7.31 (m, 3H), 7.18 (t, J = 7.7 Hz, 1H), 7.06-76.9 (m, 4H), 6.95 (d, J = 8.6 Hz, 1H), 5.55 (s, 1H); 13C NMR (100 MHz, DMSO-D6) δ 162.7 (d, J = 247.5 Hz), 157.6 (d, J = 238.0 Hz), 147.1, 138.6, 133.1, 131.7 (d, J = 8.8 Hz), 130.8 , 129.3 , 126.6, 125.9 , 123.7(2C) , 123.4 , 121.2 , 120.6 (d, J = 8 Hz), 119.3 , 117.3 , 117.0 (d, J = 4.0 Hz), 115.5 (d, J = 22.4 Hz), 115.1 , 75.6; HRMS (ESITOF) m/z: [M + Na]+ Calcd. For C25H15F2N3Na: 418.1126, found: 418.1133. 3-Cyano-1-isopropyl-2-(isopropylamino)-1H-indole (4ae): Yield: 80% (97 mg); White colour solid; Rf = 0.37 in 30% EtOAc in Hexanes; Melting Point: 158 - 159 oC; IR (KBr): ν



(cm-1) = 3327, 2972, 2188, 1566, 1470, 1321, 1166, 740; 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.4 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.16-7.07 (m, 2H), 4.56-4.49 (m, 1H), 4.27-4.21 (m, 1H), 3.44 (brs, 1H) 1.60 (d, J = 7.0 Hz, 6H), 1.35 (d, J = 6.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 150.0, 131.9, 128.7, 121.1, 120.6, 118.5, 117.2, 110.5, 66.2, 46.8, 46.3, 23.7, 20.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C15H20N3: 242.1652, found: 242.1667. 3-Cyano-1-cyclohexyl-2-(cyclohexylamino)-1H-indole (4af): Yield: 72% (115 mg); White colour solid; Rf = 0.4 in 15% EtOAc in Hexanes; Melting Point: 175 - 176 oC; IR (KBr): ν (cm1)

= 3302, 3058, 2932, 2187, 1557, 1469, 1327, 1112, 733; 1H NMR (400 MHz, CDCl3) δ 7.48

(d, J = 7.6 Hz, 1H), 7.32 (d, J = 6.0 Hz, 1H), 7.14 - 7.04 (m, 2H), 4.03 - 3.97 (m, 1H), 3.90 – 3.70 (m, 1H), 2.25 - 2.15 (m, 4H), 2.07 - 2.17 (m, 2H), 1.89 - 1.84(m, 2H), 1.83 -1.73 (m, 3H), 1.71 – 1.60 (m, 1H), 1.53 – 1.40 (m, 4H), 1.36 – 1.18 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 150.0, 132.2, 128.6, 121.0, 120.4, 118.4, 117.1, 110.8, 66.3, 55.1, 53.8, 34.0, 30.8, 26.3, 25.5, 25.3, 24.5; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. For C21H27N3Na: 344.2097 found: 344.2107. 3-Cyano-1-cyclohexyl-2-(cyclohexylamino)-5,6-dimethoxy-1H-indole (4bf): Yield: 79% (151 mg); White colour solid; Rf = 0.34 in 25% EtOAc in Hexanes; Melting Point: 131 - 133 oC;

IR (KBr): ν (cm-1) = 3761, 3348, 2934, 2856, 2191, 1560, 1491, 1405, 1259, 1057, 787;

1H

NMR (700 MHz, DMSO-D6) δ 7.00 (s, 1H), 6.76 (s, 1H), 6.27 (s, 1H), 4.23 (s, 1H), 3.76

(s, 6H), 3.68 (s, 1H), 2.18 - 2.01 (m, 4H), 1.92 – 1.54 (m, 8H), 1.45 - 1.17 (m, 8H); 13C NMR (175 MHz, DMSO-D6) δ 149.7, 145.3, 144.2, 125.0, 121.7, 118.5, 99.7, 98.7, 62.5, 56.9, 55.9, 53.1, 53.0, 33.2, 29.7, 25.5, 25.2, 24.6, 24.5; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C23H32N3O2: 382.2489, found: 382.2499. 3-Cyano-5,6-methylenedixy-1-isopropyl-2-(isopropylamino)-1H-indole (4ce): Yield: 81% (116 mg); grey colour solid; Rf = 0.3 in 25% EtOAc in Hexanes; Melting Point: 164 - 166 oC; IR (KBr): ν (cm-1) = 3319, 2973, 2195, 1564, 1473, 1316, 1255, 1161, 1038; 1H NMR (400


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MHz, DMSO-D6) δ 7.15 (s, 1H), 6.73 (s, 1H), 6.21 (d, J = 7.9 Hz, 1H), 5.92 (s, 2H), 4.7 - 4.63 (m, 1H), 4.07 – 4.02 (m, 1H), 1.44 (d, J = 6.9 Hz, 6H), 1.25 (d, J = 6.3 Hz, 6H); 13C NMR (100 MHz, DMSO-D6) δ 149.5, 142.4, 142.3, 124.8, 122.2, 118.2, 100.3, 96.0, 94.0, 63.3, 45.7, 45.2, 21.3, 20.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C16H20N3O2: 286.1550, found: 286.1524. 3-Cyano-1-(4-methoxyphenyl)-2-((4-nitrophenyl)amino)-1H-indole (4ag): Yield: 81% (155 mg); Yellow colour solid; Rf = 0.33 in 30% EtOAc in Hexanes; Melting Point: 196 - 198 oC;

IR (KBr): ν (cm-1) = 3423, 3246, 2217, 1601, 1552, 1330, 1307, 1250; 1H NMR (700 MHz,

CDCl3) δ 8.14 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 7.9 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.28 - 7.26 (m, 3H), 7.12 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.34 (s, 1H), 3.86 (s, 3H); 13C NMR (100 MHz, DMSO-D6) δ 159.4, 149.5, 143.5, 139.8, 134.6, 128.7, 126.7, 125.6(2C), 123.8, 122.8, 118.1, 115.0, 114.9, 114.8, 111.2, 78.2, 55.4; HRMS (ESITOF) m/z: [M + Na]+ Calcd. For C22H16N4O3Na: 407.1115, found: 407.1094. 3-Cyano-2-((4-nitrophenyl)amino)-1-phenyl-1H-indole (4ah): Yield: 82% (146 mg); Yellow colour solid; Rf = 0.32 in 30% EtOAc in Hexanes; Melting Point: 263 - 264 oC; IR (KBr): ν (cm-1) = 3256, 2363, 2219, 1601, 1552, 1499, 1308, 1223, 744; 1H NMR (400 MHz, DMSO-D6) δ 9.75 (s, 1H), 8.04 (d, J = 9.1 Hz, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.51 - 7.45 (m, 3H), 7.35 - 7.26 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 9.1 Hz, 2H); 13C NMR (175 MHz, DMSO-D6) δ 149.4, 143.2, 139.8, 134.3, 134.2, 129.8, 129.0, 127.4, 125.6, 125.6, 124.0, 122.9, 118.2, 115.0, 114.7, 111.2, 78.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C21H15N4O2: 355.1190, found: 355.1203. 3-Cyano-2-(tert-butylamino)-1-phenyl-1H-indole (4ai): Yield: 68% (0.098 mg); White colour solid; Rf = 0.34 in 25% EtOAc in Hexanes; Melting Point: 169 - 170 oC; IR (KBr): ν (cm-1) = 3403, 2930, 2370, 2195, 1563, 1370, 1211, 750; 1H NMR (700 MHz, CDCl3) δ 7.63 (t, J = 7.5 Hz, 2H), 7.59 - 7.54 (m, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.18 (t, J = 7.5 Hz, 1H), 7.04



Page 26 of 36

(t, J = 7.6 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 4.12 (s, 1H), 1.41 (s, 9H); 13C NMR (175 MHz, CDCl3) δ 148.7, 134.5, 134.2, 130.6, 129.7, 128.6, 128.5, 122.1, 121.6, 119.3, 117.4, 109.3, 68.0, 53.5, 30.5; HRMS (ESI-TOF) m/z: [M + Na]+ Calcd. For C19H19N3Na: 312.1471, found: 312.1442. 3-Benzoyl-1-(2,6-dimethylphenyl)-2-((2,6-dimethylphenyl)amino)-1H-indole

(7aa):

Yield: 55% (124 mg); Red colour solid; Rf = 0.30 in 5% EtOAc in Hexanes; Melting Point: 216 - 218 oC; IR (KBr): ν (cm-1) = 3041, 2923, 1697, 1573, 1534, 1475, 1203, 759; 1H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 7.81 (d, J = 4.7 Hz, 2H), 7.63 -7.47 (m, 3H), 7.05 (d, J = 6.8 Hz, 1H), 6.98 – 6.83 (m, 6H), 6.78 (d, J = 6.3 Hz, 2H), 6.46 (d, J = 5.2 Hz, 1H), 2.10 (s, 6H), 1.83 (s, 6H);

13C

NMR (100 MHz, CDCl3) δ 191.4, 157.5, 142.1, 137.3, 137.2, 135.3,

134.1, 133.1, 130.3, 128.6, 128.4, 128.4, 128.1, 127.8, 126.9, 126.0, 122.0, 121.4, 119.1, 109.6, 99.6, 18.5, 17.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C31H29N2O: 445.2274, found: 445.2284. 3-Benzoyl-[5,6-dimethoxy-1-phenyl-2-(phenylamino)]-1H-indole (7ba): Yield: 56% (125 mg); Pale red colour solid; Rf = 0.33 in 25% EtOAc in Hexanes; Melting Point: 169 - 171 oC; IR (KBr): ν (cm-1) = 3057, 2943, 2826, 1584, 1339, 1193, 1154, 722; 1H NMR (400 MHz, CDCl3) δ 10.22 (brs, 1H), 7.85 – 7.75 (m, 2H), 7.56-7.55 (m, 3H), 7.33 – 7.27 (m, 4H), 7.227.18 (m, 1H), 6.98 (t, J = 7.5 Hz, 2H), 6.87-6.82 (m, 3H), 6.62 (s, 1H), 6.40 (s, 1H), 3.77 (s, 3H), 3.60 (s, 3H);

13C

NMR (100 MHz, CDCl3) δ 191.0, 150.2, 145.9, 145.9, 141.6, 139.0,

136.2, 130.4, 129.4, 129.3, 128.4, 128.3, 128.0, 127.9, 126.9, 123.7, 122.4, 118.6, 102.8, 101.0, 94.8, 56.5, 55.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C29H25N2O3: 449.1860, found: 449.1871. 3-(3,4-Methylenedioxy-benzoyl)-5,6-methylenedioxy-1-(4-methoxyphenyl)-2-(4-methoxy phenylamino)-1H-indole (7cc): Yield: 82% (220 mg); Black solid; Rf = 0.35 in 30% EtOAc in Hexanes; Melting Point: 192 - 194 oC; IR (KBr): ν (cm-1) = 3415, 2904, 1580, 1513, 1465,


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1337, 1248, 1169, 1034; 1H NMR (700 MHz, CDCl3) δ 7.36 (d, J = 7.7 Hz, 1H), 7.28 - 7.25 (m, 2H), 7.07 (d, J = 8.5 Hz, 2H), 6.92 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.4 Hz, 2H), 6.54 - 6.51 (m, 3H), 6.42 (s, 1H), 6.08 (s, 2H), 5.85 (s, 2H), 3.76 (s, 3H), 3.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ :189.4, 159.0, 156.4, 151.8, 149.6, 147.7, 143.6, 143.5, 135.7, 132.3, 130.9, 128.8, 128.5, 125.1, 123.1, 119.4, 114.4, 113.7, 108.6, 108.1, 101.5, 100.6, 100.4, 99.6, 92.1, 55.5, 55.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C31H25N2O7: 537.1656, found: 537.1686. General Procedure for the Synthesis of 11-Amino-indolo[2,3-b]quinolines 8 An oven-dried 8 mL reaction vial was charged with respective 2-aminoindole (0.5 mmol) in dry DCE (2.0 mL) was added triflic acid (5 mmol, 0.441ml, 10 equiv) drop wise at room temperature. The reaction mixture was stirred at room temperature and monitored by TLC. After complete consumption of the starting material, the reaction mixture quenched with saturated NaHCO3 solution and extracted with DCM. The combined organic layer washed with (3x10 mL) & brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude products were purified by flash chromatography using EtOAc and hexane as eluent. 2-Methoxy-6-(4-methoxyphenyl)-6H-indolo[2,3-b]quinolin-11-amine (8aa): Yield: 95% (175 mg); Grey colour solid; Rf = 0.3 in 40% EtOAc in Hexanes; Melting Point: 192 - 194 oC; IR (KBr): ν (cm-1) = 3313, 2924, 2052, 1621, 1598, 1454, 1248, 1232; 1H NMR (400 MHz, DMSO-D6) δ 8.51 (d, J = 7.5 Hz, 1H), 7.85 (s, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.21 - 7.13 (m, 5H), 3.92 (s, 3H), 3.87 (s, 3H); 13C NMR (175 MHz, DMSO-D6) δ 158.2, 153.8, 152.6, 145.6, 142.8, 140.1, 129.2, 129.0, 128.8, 124.9, 121.6, 121.0, 120.5, 119.8, 115.1, 114.6, 108.4, 102.0, 97.8, 55.6, 55.3; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C23H20N3O2: 370.1550, found: 370.1570.



Page 28 of 36

6-Phenyl-6H-indolo[2,3-b]quinolin-11-amine (8ab): Yield: 78% (121 mg); pale orange colour solid; Rf = 0.36 in 25% EtOAc in Hexanes; Melting Point: 103 - 105 oC; IR (KBr): ν (cm-1) = 3373, 2924, 2853, 1626, 1402, 1214, 750, 702; 1H NMR (400 MHz, DMSO-D6) δ 8.54 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 8.4 Hz, 1H), 7.73 – 7.61 (m, 5H), 7.58 (t, J = 7.6 Hz, 1H), 7.54 - 7.48 (m, 1H), 7.42 – 7.22 (m, 6H);

13C

NMR (175 MHz, DMSO-D6) δ 153.4, 147.2,

146.6, 139.5, 136.4, 129.4, 128.8, 127.8, 127.4, 127.3, 125.0, 122.8, 121.6, 121.3, 120.7, 120.3, 115.1, 108.6, 97.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C21H16N3: 310.1339, found: 310.1358. 2-Fluoro-6-(4-fluorophenyl)-6H-indolo[2,3-b]quinolin-11-amine (8ac): Yield: 80% (139 mg); colourless solid; Rf = 0.37 in 20% EtOAc in Hexanes; Melting Point: 202 - 203 oC; IR (KBr): ν (cm-1) = 3423, 1640, 1514, 1259, 1040; 1H NMR (700 MHz, DMSO-D6) δ 8.54 (d, J = 7.5 Hz, 1H), 8.34 - 8.30 (m, 1H), 7.78 – 7.58 (m, 3H), 7.49 - 7.45 (m, 3H), 7.39 (t, J = 7.5 Hz, 1H), 7.36 – 7.26 (m, 3H), 7.23 (d, J = 7.8 Hz, 1H); 13C NMR (175 MHz, DMSO-D6) δ 159.6 (d, J = 717.5 Hz), 158.2 (d, J = 710.5 Hz), 153.2, 146.1 (d, J = 3.5 Hz), 144.2, 139.8, 132.6 (d, J = 3.5 Hz), 130.0 (d, J = 8.92 Hz), 129.6 (d, J = 8.75 Hz), 125.4, 121.9, 120.9, 120.5, 118.3 (d, J = 24.5 Hz), 116.3 (d, J = 22.75 Hz), 115.1 (d, J = 8.75 Hz), 108.6, 106.6 (d, J = 22.75 Hz), 97.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C21H14N3F2: 346.1150, found: 346.1149. 2-Fluoro-6-(4-fluorophenyl)-7,9-dimethoxy-6H-indolo[2,3-b]quinolin-11-amine

(8dc):

Yield: 82% (166 mg,); colourless solid; Rf = 0.34 in 30% EtOAc in Hexanes; Melting Point: 274 - 276 oC; IR (KBr): ν (cm-1) = 3410, 2839, 2037, 1631, 1513, 1303, 1206, 1031, 825; 1H NMR (400 MHz, DMSO-D6) δ 8.27 (dd, J = 9.6, 2.7 Hz, 1H), 7.73 – 7.58 (m, 2H), 7.49 – 7.37 (m, 3H), 7.29 (t, J = 8.8 Hz, 2H), 7.24 (brs, 2H), 6.68 (d, J = 1.8 Hz, 1H), 3.92 (s, 3H), 3.59 (s, 3H);

13C

NMR (100 MHz, DMSO-D6) δ 160.6 (d, J = 242.7 Hz), 156.7 (d, J = 237.0 Hz),

155.2, 154.1, 146.2, 145.8, 144.2, 134.8, 130.5, 130.4, 129.5 (d, J = 8.0 Hz), 122.7 (d, J = 16.0


Page 29 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Hz), 118.2 (d, J = 24.9 Hz), 114.6, 114.4, 106.6 (d, J = 23.0 Hz), 98.6, 98.5, 98.5, 56.2, 55.8; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C23H18N3O2F2: 406.1362, found: 406.1453. 9-Methoxy-13-(4-methoxyphenyl)-13H-benzo[6,7]indolo[2,3-b]quinolin-7-amine

(8ea):

Yield: 72% (152 mg); Green colour solid; Rf = 0.34 in 30% EtOAc in Hexanes; Melting Point: 202 - 203 oC; IR (KBr): ν (cm-1) = 3433, 3329, 3241, 2995, 2834, 1722, 1643, 1614, 1512, 1439, 1713, 1234, 1035; 1H NMR (400 MHz, DMSO-D6 + CF3COOD) δ 8.73 (d, J = 6.8 Hz, 1H), 8.11 – 7.83 (m, 4H), 7.68 (d, J = 5.6 Hz, 2H), 7.50 - 7.35 (m, 2H), 7.38 – 7.18 (m, 3H), 7.16 – 7.01 (m, 1H), 3.95 (s, 3H), 3.89 (s, 3H); 13C NMR (175 MHz, DMSO-D6 + CF3COOD) δ 161.8, 156.6, 151.7, 145.3, 133.3, 132.9, 131.8, 131.5, 129.6, 128.4, 126.6, 125.8, 124.1, 124.0, 121.4, 121.0 (2C), 120.1, 117.4, 116.7, 114.9, 104.4, 98.3, 56.4, 56.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd. For C27H22N3O2: 420.1707, found: 420.1719. Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Mechanism for the formation of the E/Z isomers 3ag, 3ah, and 3ai. 1H NMR and 13C NMR spectra of all of the compounds and Molecular structures of compounds 4ag and 4ai at 30% probability of thermal ellipsoids. (PDF) X-ray crystallographic data for compounds 4ag and 4ai (CIF) The X-ray data were also deposited with the CCDC (Entries 1833742 & 1833743)]. Acknowledgments This work was supported by the Department of Atomic Energy, Government of India. References (1) Corbet, J. P.; Mignani, G. Selected Patented Cross-Coupling Reaction Technologies. Chem. Rev. 2006, 106, 2651 – 2710. (2) (a) Magano, J.; Dunetz, J. R. Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals. Chem. Rev. 2011, 111, 2177 – 2250. (b) Torborg, C.; Beller, M. Recent Applications of Palladium-Catalyzed Coupling Reactions in the Pharmaceutical, Agrochemical, and Fine Chemical Industries. Adv. Synth. Catal.



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Copper Catalyzed Intramolecular N-Arylation of Ketene Aminals at

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